Does Addyi (flibanserin) have any major drug interactions one needs to be aware of before prescribing?

Major Drug Interactions with Addyi (Flibanserin)

Addyi has several critical contraindications and major drug interactions that can cause life-threatening hypotension and syncope, most notably with alcohol and CYP3A4 inhibitors, requiring absolute avoidance of these combinations. 1

Absolute Contraindications (Do Not Prescribe)

Alcohol

• Alcohol use is contraindicated with Addyi due to severe risk of hypotension and syncope 1, 2
• Patients must wait at least 2 hours after consuming 1-2 standard alcoholic drinks before taking Addyi at bedtime 1
• If patients consume 3 or more standard drinks, they must skip their Addyi dose that evening 1
• After taking Addyi at bedtime, patients cannot consume alcohol until the following day 1
• Phase 1 studies demonstrated increased incidence of hypotension and syncope when flibanserin was coadministered with ethanol, with sedation increasing 20-27% from baseline 2

Moderate or Strong CYP3A4 Inhibitors

• Concomitant use with moderate or strong CYP3A4 inhibitors is contraindicated as these significantly increase flibanserin concentrations, leading to hypotension and syncope 1
• Discontinue Addyi at least 2 days before starting a moderate or strong CYP3A4 inhibitor 1
• Discontinue the CYP3A4 inhibitor for 2 weeks before restarting Addyi 1
• Common contraindicated CYP3A4 inhibitors include:
  • Azole antifungals (ketoconazole, itraconazole, posaconazole, fluconazole, voriconazole) 3, 4
  • Macrolide antibiotics (erythromycin, clarithromycin, telithromycin) 3
  • HIV protease inhibitors (ritonavir and all boosted or unboosted protease inhibitors) 3
  • Cobicistat-based regimens 3

Hepatic Impairment

• Addyi is contraindicated in patients with any degree of hepatic impairment as this significantly increases flibanserin concentrations, leading to hypotension and syncope 1

Major Warnings and Precautions

Multiple Weak CYP3A4 Inhibitors

• Concomitant use of multiple weak CYP3A4 inhibitors can lead to clinically relevant increases in flibanserin concentrations 1
• This includes herbal supplements (ginkgo, resveratrol) and non-prescription drugs (cimetidine) 1
• Carefully review all medications, supplements, and over-the-counter products before prescribing 3

Oral Contraceptives and Other Weak CYP3A4 Inhibitors

• These increase flibanserin exposures and incidence of adverse reactions 1
• Monitor closely for increased CNS depression, dizziness, and somnolence 1

Strong CYP2C19 Inhibitors

• These increase flibanserin exposure, which may increase risk of hypotension, syncope, and CNS depression 1
• Requires increased monitoring and consideration of dose adjustment or alternative therapy 1

CYP3A4 Inducers

• Use of Addyi is not recommended with CYP3A4 inducers as flibanserin concentrations are substantially reduced, decreasing efficacy 1
• Common inducers include carbamazepine, phenytoin, rifampin, and St. John's wort 3, 5

Digoxin Interaction

• Addyi increases digoxin concentrations, which may lead to digoxin toxicity 1
• Increase monitoring of digoxin concentrations when co-prescribing 1
• This is particularly important given that digoxin has a narrow therapeutic index 3

CNS Depressants

• Addyi causes CNS depression (somnolence, sedation, fatigue) in 21% of patients vs 8% with placebo 1
• Risk of CNS depression increases when combined with other CNS depressants 1
• Patients should not drive or engage in activities requiring full alertness until at least 6 hours after taking Addyi 1

Pre-Prescribing Checklist

Before prescribing Addyi, verify:

• No alcohol use or patient willing to strictly adhere to alcohol restrictions 1
• No moderate or strong CYP3A4 inhibitors (including azole antifungals, macrolides, HIV protease inhibitors) 1
• Normal hepatic function (any hepatic impairment is a contraindication) 1
• Review all medications including over-the-counter drugs and herbal supplements for weak CYP3A4 inhibitors 1
• If patient takes digoxin, plan for increased monitoring 1
• No strong CYP2C19 inhibitors or plan for increased monitoring 1
• Patient counseled to take medication at bedtime only, not during waking hours 1

Common Pitfalls to Avoid

• Do not underestimate the alcohol interaction - this is a pharmacodynamic interaction causing severe hypotension and syncope, not just additive sedation 2
• Do not prescribe if patient cannot reliably abstain from alcohol - the 2-hour waiting period and skip-dose rules require strict adherence 1
• Do not overlook herbal supplements and OTC medications - multiple weak inhibitors can accumulate to cause significant interactions 1
• Do not forget that oral contraceptives are weak CYP3A4 inhibitors - monitor for increased adverse effects 1
• Drug-drug interactions increase exponentially with polypharmacy (10.9% with 2-4 drugs, 80.8% with ≥10 drugs) 3